Human and murine major histocompatibility complex encoded class I and II molecules that are integrally involved in the presentation of antigen to cytotoxic and helper T lymphocytes, respectively, are isolated and their molecular properties are studied. The goal of these studies is to gain a molecular understanding of their functional and antigenic properties. Analysis of the HLA-A3 variant (E1) that is altered in its ability to present influenza antigens to CTL has revealed that it was most likely derived by a gene conversion event. Such events appear to be the predominant mechanisms of generating diversity among these genes. In the mouse studies, it has been determined that class I molecules achieve additional diversity through the use of alternative transcripts of the same gene. The alternative forms of certain class I molecules appear to be differentially expressed in T and B cells suggesting that they may have functional signficance. Factors controlling expression of the murine soluble class I molecule (Q10) were investigated. Serum levels, under control of the H-2D region, varied signficantly for different haplotypes and were affected by various external factors. Additional studies in the mouse have revealed a second family of D-region molecules representing several distinct haplotypes. This so called Dw3-family was found to be quite distinct from the previously defined Ld-family of molecules. Class I molecules through their interaction with antigens are important for regulation of the antibody response by T helper cells. Structural variations in IAk molecules involved in this regulatory process have been localized to the alpha l and beta 1 domains.